Injectable compositions of the (plus)-optical isomer of the alpha racemate of 2-(2-ethyl-2-phenyl-1, -dioxolan-4-yl)piperidine and their use

ABSTRACT

Injectable compositions of the (+) optical isomer of the alpha racemate of 2-(2-ethyl-2-phenyl-1,3-dioxolan-4-yl)piperidine, in free base or acid addition salt form, and their use as a general anesthetic, immobilizing or calming agent or depressant.

United States Patent m1 Thompson et al.

I45] Sept. 18,1973

INJECTABLE COMPOSITIONS OF THE (PLUS)-OPTICAL ISOMER OF THE ALPHARACEMATE OF Z-(Z-ETHYLeZ-PHENYL-l, -DIOXOLAN-4-YL )PIPERIDINE AND THEIRUSE Inventors: Charles R. Thompson, Walnut Creek; John Hidalgo, Oakland,both of Calif.

Assignee: Cutter Laboratories, Inc., Berkeley,

Calif.

Filed: Oct. 15, 1971 Appl. No.: 189,760

Related US. Application Data Continuation-in-part of Ser. No. 800,282,Feb. 18, 1969, Pat. No. 3,655,680

US. Cl. 424/267 Primary Examiner-Albert T. Meyers AssistantExaminerAllen J. Robinson Att0rneyl. William Millen et al.

[57] ABSTRACT lnjectable compositions of the optical isomer of the alpharacemate of 2-(2-ethyl-2-phenyl-l,3-dioxolan-4- yl)piperidine, in freebase or acid addition salt form, and their use as a general anesthetic,immobilizing or calming agent or depressant.

21 Claims, No Drawings INJECTABLE COMPOSITIONS OF THE (PLUS)-OPTICALISOMER OF THE ALPHA RACEMATE OF 2-(2-ETHYL-2-PHENYL-l-DIOXOLAN-4-YL)PIPERIDINE AND THEIR USE This is a continuation-in-partof application Ser. No.

800,282, filed Feb. 18, 1969, now US. Pat. No. 3,655,680.

BACKGROUND OF THE INVENTION This invention relates to compositionscomprising an optical isomer of 2-( 2-ethyl-2-phenyl-l,3-dioxolan-4-yl)piperidine and to their use.

US. Pat. 3,262,938, issued July 26, 1966, discloses a class of2-substituted-4-(2-piperidyl)-dioxolanes, in-

SUMMARY OF THE INVENTION According to this invention, there is providednovel compositions adapted for parenteral administration comprising apharmaceutically acceptable acid addition salt of the optical isomer ofthe alpha racemate of 2-(2-ethyl-2-phenyl-l ,3-dixolan -4-yl)piperidine, substantially free from its isomers. In a method of useaspect, such a composition is injected parenterally, preferablyintramuscularly, into a mammal, preferably a feline or primate, in acalming (at lower dosages) or immobilizing (at higher dosages) amount,less than that which induces general anesthesia. In a preferred aspect,the composition is injected parenterally, preferably intravenously, in amammal, preferably a primate, in an amount effective to induce generalanesthesia.

DETAILED DISCUSSION The optical isomer of the alpha racemate of 2-( 2-ethyI-Z-phenyll ,3-dioxolan-4-yl)piperidine possesses useful andunexpected pharmacological activity, including general anesthetic,immobolizing muscle relaxant, analgesic, spasmolytic, andanti-convulsant activity. This optical isomer has four times theintravenous general anesthetic activity of its parent racemate, i.e.,the compound of Example 12 of US. Pat. No. 3,262,938. This is totallyunexpected because if one optical isomer of an activeracemate is activeand the other is inactive, the racemate ought possess half the activityof its active optical isomer. The fact the optical isomer of thisinvention is four times as active as an i.v. anesthetic as its racemateestablishes the optical isomer is not only inactive, it apparentlyinterferes with the general anesthetic activity of the isomer whencombined therewith as a racemic mixture. Also, the compound of thisinvention has a better anesthetic activity to side-effects ratio thanthe racemate.

The immobilizing and general anesthetic activity is manifested uponparenteral administration in primates without markedly depressingrespiration. It is a dissociative anesthetic of the type described byDomino et al., in Clinical Pharmacology and Therapeutics, 6:279 (1965).A dissociative anesthetic is one which renders the anesthetizedindividual incapable of relating to his surroundings and proceduresundertaken upon him. This compound is also a useful adjunct to knowngeneral anesthetics. In addition to its general anesthetic activity, thecompound of this invention provides good muscle relaxation, an importantand valuable coactivity for a general anesthetic. The character of thegeneral anesthetic activity of the compound of this invention variesconsiderably from species to species, i.e., in dogs and rats, which aretwo commonly used laboratory test animals, the compound does not readilyproduce the narcosis generally associated with this activity, but doesso in primates, e.g., monkeys and man, and in felines, e.g., domesticcats. Thus, it was surprising to discover that this compound possesseshighly useful general anesthetic activity since it appeared to lack thisactivity when tested in screening tests employing dogs or rats becausethe animals were not completely immobilized, even at relatively highdosages (2.5, 5 and 10 mgJkg. i.v.). Further studies did, however,reveal general anesthetic activity in dogs at dosages which did notinduce narcosis. See Traber et al., J. Pharm. & Exp. Ther. 175, 395-403(1970). Additionally, the compound exhibits anti-convulsant, analgesic,central nervous system depressant, spasmolytic and local anestheticeffects. The analgesic activity of the compound of this invention isunusual in that complete analgesia can be induced, as demonstrated byindifference to noxious and painful stimuli, without inducing a comatosestate.

The compositions of this invention are particularly advantageous whenused as a general anesthetic for several reasons. They have a longduration of anesthesia, a short induction period and relatively littleadverse side-effects. They produce amnesia of the surgical episode.Post-operative analgesia reduces considerably the necessity forpost-operative medication to reduce pain.

The compositions of this invention are particularly useful as a basalanesthetic, i.e., administered intravenously or intramuscularly in anamount just sufficient to achieve light or marginal anesthesia, with orwithout accompanying narcosis, and supplement this effect by concurrentor subsequent administration of another anesthetic, e.g., sodiumpentothal, preferably an inhalation anesthetic, e.g., nitrous oxide,diethyl ether, 2,2- dichloro-l,l-difluoroethyl methyl ether, etc., toachieve surgical anesthesia. Such a combination has the advantage thatthe inhalation anesthetic can be administered at lower concentrations,simultaneously with oxygen, oxygen and nitrogen mixtures, e.g., 40%

oxygen and 60% nitrogen, or air, thus avoiding or reducing the incidenceof respiratory distress associated with the use-of these anesthetics ina conventional manner to induce surgical anesthesia.

The compositions of this invention also have useful general anestheticactivity when administered intramuscularly. In addition, by this routeof administration, using sub-anesthetic dosages, they can be used tosubdue wild animals, especially of the feline family, and immobilizedomestic animals and primates. The compositions of this invention areparticularly useful for their immobilizing effect because they have ahigher ED /LD ratio than the compositions, e.g., curare derivatives,presently employed for this purpose. Moreover, because they are nottoxic when administered intravenously, the accidental administrationintraveneously does not produce the serious sequel of events which occurwith drugs which can only be administered intramuscularly. They areuseful adjuncts to psychiatric therapy, inducing a suggestible statewhich facilitates the diagnosis and treatment of a wide variety ofmental disorders.

The active compound of the compositions of the invention is slightlywater-soluble and is most stable at pH 6 or higher. It is less stablebelow pH 6. Inasmuch as general anesthetics are commonly administeredintravenously, in order to rapidly induce and carefully maintainanesthesia, a preferred embodiment of the compound of this invention isin a sterile aqueous solution of a pharmacologically acceptable acidaddition salt, preferably a buffered solution, e.g., containing from 0.1to percent, of the compound of this invention. A suitable buffer issodium succinate. Antimicrobial agents may be added to the solution ofthe compound of this invention, e.g., when packaged in multiple dosecontainers, e.g., benzethonium chloride or benzalkonium chloride, at aconcentration of about 0.01 percent.

Other routes of administration besides intravenous are useful,particularly when the compound is used other than as an i.v. anesthetic.In a preferred embodiment of this invention, the active compound is inthe form of a pharmaceutically acceptable acid addition salt in acomposition adapted for intramuscular injection. These compositions canbe either aqueous or oily suspensions or aqueous solutions. The activecompound is preferably present therein at a concentration of between 0.5and 5.0%.

The active compound of the compositions of this invention, viz.,alpha(+)-2-ethyl-2-phenyl l ,3-dioxolan- 4-yl)piperidine, can beemployed in free base form or preferably as a pharmaceuticallyacceptable acid addition salt. The latter can be prepared in theconventional manner by reacting the free base form with an inorganic ororganic acid. Because of their greater solubility in conventionalpharmaceutically acceptable carriers the salt forms are employed for theadministration of the compounds for the pharmacological purposes setforth herein. In other respects the acid addition salt form of thecompound of this invention is the equivalent of the free base form.Examples of pharmaceutically acceptable salts are water soluble salts ofinorganic acids, e.g., hydrochloric, hydrobromic,.hydiodic, nitric,sulfuric and phosphoric acid, and salts of organic acids, includingaliphatic, alicyclic, araliphatic, aromatic and heterocyclic, monoorpolybasic carboxylic acids, e.g., formic acid, acetic acid, propionicacid, diethylacetic acid, malonic acid, succinic acid, pimelic acid,fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid,amino-carboxylic acids, citric acid, gluconic acid, ascorbic acid andsulfonic acids, e.g., methanesulfonic, ethanesulfonic andp-toluenesulfonic acids.

The active compound of the compositions of this invention is formulatedwith conventional pharmaceutical excipients adapted for parenteraladministration. Aqueous solutions are preferred for intraveneousadministration. Oily and aqueous solutions and emulsions, as well asaqueous solutions can be employed for intramuscular administration.

The compositions of this invention are usually administered by infusionintravenously as a dilute solution, e.g., 0.5 2.0% of the activecompound in sterile water, preferably also containing about 0.01% ofbenzethonium chloride and about 0.05 0.07 M sodium succinate orphosphate buffer sufficient to maintain a pH of about 6.5 7.3.

The exact dosage depends more upon the species than route ofadministration. For example, although 0.5 2O mg./kg. intramuscularly andintravenously will generally suffice for all species, only about 0.5 2.5mg./kg. is required for humans, 2.5 5.0 mg./kg. is required for monkeys,whereas 15 25 mg./kg. is required for cats for major surgicalanesthesia.

Because 2-(2-ethyl-2-phenyl-l,3-dioxolan-4- yl)piperidine has threeasymmetric carbon atoms, it can exist as four different racemicmixtures. Three of these are specifically disclosed in U.S. Pat. No.3,262,938. The two racemates produced from the alpha racemate of2-piperidyl-1,2-ethanediol (the hydrochloride of which melts at 101) aredesignated alpha racemate" (Example 12) and gamma racemate" (Examplel3). Of the two racemates which were produced from the beta racemate of2-piperidyl- 1,2-ethanediol (whose hydrochloride melts at l39-l4l), theone which was isolated was designated the beta racemate. The compound ofthis invention is the dextrorotatory optical isomer of the alpharacemate of 2-(2-ethyl- 2-phenyl-l ,3-dioxolan-4- yl)piperidine. Nuclearmagnetic rotation spectra have established the piperidine ring and thephenyl ring are trans with respect to the dioxolane ring.

The compound of this invention can be prepared from the alpha racemateof Example 12 of U.S. Pat. No. 3,262,938 in the conventional manner,e.g., by forming an acid addition salt of the free base thereof with anoptically active acid and fractionally crystallizing the resultingmixture to separate the optical isomers. Preferably, however, it isprepared according to the process set forth in the preparationshereinafter.

It was established that the optical isomer of this invention is theoptical isomer of the alpha racemate of Example 12 of U.S. Pat. No.3,262,938, rather than the optical isomer of the gamma racemate ofExample 13, by following the procedure described in Preparation 1 hereinusing the optical isomer of the alpha racemate of2-(2,2-diphenyl-l,3-dioxolan-4- yl)piperidine of Example 10 of U.S. Pat.No. 3,262,938, to produce the optical isomer of the alpha racemate ofZ-piperidyl-l ,Z-ethanediol of Preparation 14 of U.S. Pat. No.3,262,938. This compound was then reacted with propiophenone dipropylacetal and a levorotatory optical isomer of 2-(2-ethyl-2-phenyl-l,3-dioxolan-4-yl)piperidine was isolated. A 50:50 physicalmixture of this optical isomer and the optical of this invention whenrecrystallized produced the alpha racemate of Example 12 of U.S. Pat.No. 3,262,938.

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The following preferred specific embodiments are,there-v fore, to be construed as merely illustrative, and not limitativeof the remainder of the disclosure in any way whatsoever.

Preparation 1 Alpha (+)2-(2-ethyl-2-phenyl-l ,3-dioxolan-4-yl)piperidinehydrochloride A solution of 477 g. of the optical isomer of the alpharacemate of 2-(2,2-diphenyl-l,3-dioxolan-4- yl)piperidine hydrochloride(U.S. Pat. No. 3,262,938, Example 9) in 1500 ml. methanol, 25 ml. waterand 20 ml. concentrated hydrochloric acid was refluxed two hours. Mostof the methanol was removed by distillation and the concentrate wasdiluted with 1,500 ml. ether. The crystalline product which precipitatedwas filtered, washed with ether and recrystallized from isopropanol anddried to give 240.9 g. of alpha()2- piperidyl-l,2-ethanediolhydrochloride, melting at about 137-139; aD 25 -8.l2 Analysis:

Calcd. for C l-l NO 7.71; Cl, 19.52

Found: C, 46.02; H, 8.84; N, 7.87; Cl, 19.46

A mixture of 1,017 g. of alpha (-)2-piperidyl-1,2- ethanediolhydrochloride and 1,592 g. of propiophenone dipropyl acetal (U.S. Pat.No. 3,262,938) in 6 liters of anhydrous isopropanol was brought toreflux and a solution of anhydrous hydrogen chloride in propanol wasadded to bring the pH between 1 and 2. The solution was refluxed about 2hours, allowed to remain at room temperature overnight and thecrystalline product which formed was recrystallized twice fromisopropanol and dried to give alpha(+)-2-(2-ethyl-2- phenyl- 1,3-dioxolan-4-yl)piperidine hydrochloride, melting at about 221.5 222.0;D 25 --l6.63

HCl: C, 46.28; H, 8.88; N,

Analysis:

Calcd. for C,,H,,N0, HCl: C, 64.52; H, 8.12; N, 4.70; CI, 11.90

Found: C, 64.37; H, 7.93; N, 4.79; Cl, 8c 11.83

The solvent was removed from the mother liquors and the residue washeated for several hours in refluxing propanol containing anhydroushydrogen chloride and additional propiophenone dipropyl acetal.Isolation of crystalline product in the manner described above yieldedan addtional amount of the alpha(+)-isomer.

Preparation 2 Alpha (+)2-(2-ethyl-2-phenyl-l ,3-dioxolan-4-yl)piperidinemaleate An aqueous solution of the hydrochloride saltof Preparation 1was rendered basic with dilute sodium hydroxide solution and the freebase was extracted with ether. Theether solution was dried overmagnesium sulfate, filtered, and the ether was removed. A molarequivalent of maleic acid in ethanol was added to the free base and thesolution was diluted with dry ether. The crystalline product wasrecrystallized from isopropanol to givealpha(+)2-(2-ethyl-2-phenyl-1,3-dioxolan-4-yl)pipericline male'ate,melting at about 127.5 -128.5.

Analysis:

Calcd. for CmHgaNOg C4H40 i C, H, N, 3.71

Found: C, 63.66; H, 7.10; N, 3.57 EXAMPLE 1 For intravenousadministration, form a 0.5 2% sterile aqueous solution ofalpha(+)2-(2-ethyl-2-phenyl- 1,3-dioxolan-4-yl)piperidine hydrochloride.For administration to humans, infuse in a lactated Ringers solution.EXAMPLE 2 For intramuscular administration, prepare a 2 5% sterileaqueous solution of alpha(+)2-ethyl-2-phenyll,3-dioxolan-4-yl)piperidinehydrochloride.

To obtain a longer-acting composition dissolve the (+)optical isomer ofthe alpha racemate of 2-(2-ethyl- 2-phenyl-1,3-dioxolan-4-yl) piperidinein a suitable oil, e.g., corn, peanut, cotton-seed or sesame oil.EXAMPLE 3 USE AS INTRAVENOUS ANES- Tl-lETlC 1N MONKEYS The surgicalopening of the abdomen or laparotomy was accomplished in African GreenMonkeys (cercopithecus aethiops) using the minimal effective dose shownin the table below, of a composition of Example 1, administeredintravenously as a one percent aqueous solution. The onset is the timein minutes at which the monkey was released unrestrained. Duration isthe time in minutes after onset of anesthesia when the monkey began tolift his head or attempted to rise from the table. Abdominal muscleswere easily manipulated during the procedure due to the muscle relaxantproperties of the compound. The surgical procedure was an incision ofabout 5 to 10 centimeters at the midline of the abdomen. Each musclelayer was separated and the peritoneum opened. The liver was probedbefore the wound was closed layer-by-layer. The surgery was completed inten to 15 minutes. The results of the experiments are set forth below:

Anesthesia Monkey Dose Onset Duration Wt. & Sex mglkg (minutes)(minutes) 3.35 Kg. 5 2 30 Male 2.4 Kg. 5 2 64 Male 2.45 Kg. 5 1 67Female 2.45 Kg. 2.5 0.5 27 Female 2.5 Kg. 2.5 0.5 28 Female 3.4 Kg. 2.50.4 32 Female Similar results are observed when the compound of thisinvention is used as a general anesthetic for surgical purposes in otherprimates, e.g., man, apes, chimpanzees, etc.

EXAMPLE 4 USE AS INTRAVENOUS ANES- THETlC 1N HUMANS The following is asummary of the results of testing in human volunteers reported by Wilsonet al., Anesthesia and Analgesia Current Researches, Vol. 49, No. 2, pp.236-241 (1970).

Thirteen male Caucasian medical students, all pair volunteers, wereaccepted for the study from a screen of 29 individuals. Mean age of thegroup was 23.6 years (range 22 to 25 years). Their mean weight was 173pounds (range of to 205 pounds). The subjects were fasted at least fourhours before being tested.

The moment for administering the test drug came at a time unknown to thesubject through a separate peripheral intravenous catheter (16gaugeteflon), which had been placed previously and was attached to aninfusion bottle of lactated Ringers solution.

Eleven of the subjects tested received a single dose of 0.75 mg./kg. ofalpha(+)2-(2-ethyl-2-phenyl-1,3- dioxolan-4-yl)piperidine hydrochlorideas a 0.5 percent solution intravenously. One subject received 0.25

mgJkg. and one received 0.50 mg./kg. The dose 0.75 mgJkg. was selectedas the maximal necessary for the test, since useful coma was seen atthis level in all subjects.

The agent was injected over a 2-minute period. During the time ofinjection the subject was, as he had been for the hour or more precedingthe drug injection, reclining, listening to music through the earphonse,and separated from visual distractions by the eye patches. During theperiod preceding the drug injection, control data were taken. Thesubject, after having received the drug, was asked a series of questionsand given commands, commencing early and extending into the postrecoveryperiod. Physiologic data were recorded at intervals.

The duration of useful coma varied from 50 to 85 minutes in the 11subjects receiving the 0.75 mg./kg. dose. The period of profoundanalgesia exceeded the period described as useful coma by varyingamounts in individual subjects; however, an impressive degree ofanalgesia was present in all subjects up to 2 hours or more. The periodof amnesia for recent recall exceeded the useful coma by from 2 to 4hours in all subjects tested. During the period of reduced analgesia,but complete amnesia, the subject was in possession of all his cognitivefactors and was able to perform analytical mental thought processes, aswell as past recall, although recent recall was distinctly attenuated insome subjects.

Psychologic and performance of perceptual motor functions as well aspsychiatric changes can be summarized by stating that no problems werenoted at the time of the 48-hour review, and the drug was concluded fromall standpoints to be devoid of effects extending beyond this period.

EXAMPLE 5 USE AS INTRAMUSCULAR ANES- THETICS IN CATS Ketaminehydrochloride, a known dissociative anesthetic for cats, was comparedwith alpha(+)2-( 2-ethyl- 2-phenyll ,3-dioxolan-4-yl) piperidinehydrochloride. Under sterile conditions, a complete ovariohysterectomy,including removal of the ovaries and the body of the uterus, followingthe technique for inversion of the uterine stump, was performed onfemales, seven with alpha(+)2-( 2-ethyl-2-pheny1-l ,3-dioxolan-4-yl)piperidine hydrochloride and three with ketamine hydrochloride. Onelaparotomy and one castration was performed on two males withalpha(+)2-( 2-ethyl-2- phenyll ,3-dioxolan-4-yl )piperidinehydrochloride. The laparotomy was used instead of castration because themale was either immature or had been previously castrated.

The time of intramuscular administration (IM) to the end of surgeryranged from 45 90 minutes with the actual surgery taking up about 25minutes.

With both compounds the animals became ataxic in 2 4 minutes;preparation for surgery could begin in 4 6 minutes; irritation ofinjection site was not noted other than needle sting; the animals wouldstart walking, though staggering, in 2 3 hours; appeared normal thoughinactive in 24 hours; and appeared normal with activity only slightlylimited in 2 3 days.

A large amount of salivation was observed in all ketamine anesthetizedcats, and none in any alpha(+)2-(2 ethyl-2-phenyl- 1 ,3-dioxolan-4-yl)piperidine hydrochloride cats.

Ketamine hydrochloride was used at the minimum dose recommended by thesupplier, viz., 33 mg./kg. 1M, in a solution of 100 mg./cc. The firstalpha(+)2-(2- ethyl-2phenyll ,3-dioxolan-4-yl )piperidine hydrochloridecat was anesthetized at one half the minimum recommended dose ofketamine, viz., 16.5 mg./kg. 1M in a 100 mgJcc. solution. However,a1pha(+)2-( 2- 8 ethyl-Z-phenyll ,3-dioxolan-4-yl )piperidinehydrochloride began to precipitate after standing, and all otheralpha(+)2-(2-ethyl-2-phenyl- 1,3-dioxolan-4- yl)piperidine hydrochloridesolutions were made up at 50 mg./cc.

At 7.5 mg./kg. and 10 mg./kg. doses, 2.5 mg./kg. and 0.1 mg./kg.supplemental doses, respectively, were required. At 15 and 16.5 mg./kg.,anesthesia was sufficient for the surgical procedure.

From the results of these experiments, it was determined that forsurgery lasting less than one hour, 15 mgJkg. IM is an effective dose ofalpha(+)2-(2-ethyl- 2-phenyl-l ,3-dioxolan-4-yl)piperidinehydrochloride, whereas 33 44 mgJkg. IM of ketamine hydrochloride wasrequired for anesthesia lasting 30 45 minutes. To insure profoundanesthesia for surgery of 60 minutes, 22 mg./kg. of alpha(+)2-(2-ethyl-2-phenyll,3-dioxolan-4-yl)piperidine hydrochloride ispreferred. EXAMPLE 6 USE FOR IMMOBILIZATION OF MONKEYS VIA INTRAMUSCULARADMINISTRA- TION 2.0 and 4.0 mg./kg., respectively, of the maleic acidaddition salt of alpha(+)2-(2-ethyl2-phenyl-1,3-dioxolan-4-yl)piperidineas a l and 2% aqueous solution, respectively, were administeredintramuscularly in the thigh of two female green monkeys. The effectswere noted as follows:

Monkey 1 (minutes after injection):

6. first indications of drug effect;

7. sat and did not move;

8. rubbed eyes and appeared sleepy;

l2. lateral nystagmus;

16. did not struggle when removed from the cage, calm and did not resisthandling pressure applied to the orbital ridge did not elicit anyresponse;

19. ataxic loud noises did not startle it;

24. sat quietly;

39. still in a sitting position but reacted to loud noises;

49. more aware of the surroundings;

71. picked up food, but did not eat;

74. standing but still slightly ataxic.

Monkey 2 (minutes after injection):

2. rubbed thigh where injected;

3. ataxic;

4. sat quietly;

5. vertical nystagmus;

6. began to yawn and head trembled monkey could not hold its head up anylonger and gradually laid down;

8. fist clenched and eyes wide open;

10. abdominal muscles relaxed, but the fists still clenched anddifficult to open no salivation present;

21. arms and legs were relaxed;

29. attempted toraise its head;

35. yawned and still attempted to raise its head;

41. no reaction to pinching of the skin with a hemostat or pressureapplied to the orbital ridges;

Sl. reacted to pressure applied to the orbital ridges;

64. suddenly sat up.

EXAMPLE 7 USE AS INTRAMUSCULAR ANES- THETIC IN MONKEYS Following theprocedure of Example 6, surgically effective general anesthesia isinduced by injecting intramuscularly either of the solutions employedtherein at a level of 8 mg./kg.

EXAMPLE 8 USE AS BASAL ANESTHETIC IN HU- 5. The composition of claim 3as a O.l to 5 percent solution.

6. The composition of claim 1 adapted for intramuscular injection in theform of a pharmaceutically ac- MANS 5 cept'able acid addition salt.

T hydrochlonde f addmon of f1lPha(+)2 7. The composition of claim 6 as asterile aqueous so- (2-ethyl-2-phenyl-l ,3-dioxolan-4-yl )piperidme (CL-lutiom 1848C) was admmlstered to f Pauems at dosages 8. The compositionof claim 7 wherein the addition of 0.75 or 1.0 mg./kg. body weight priorto surgery. An- Salt is the hydrochloride esthesia was completed with a60 40% mixture of nilo 9, The composition f claim 7 as a 5 to 5 percenttrous oxide and oxygen. The table below lists the details l i thereof.10. A method of at least calming a mammal which An increase in bloodpressure and heart rate was recomprises administering parenterally tothe mammal ported in all patients. Three of the patients reported thecomposition of claim 1 in a non-toxic amount effecsurgical amnesia. tiveto at least calm the mammal.

Dosage CL-l848C Approx. Patient, Length of period of Other anestheticage/sex Surgery surgery Premedicntion Initial Additional induction used1 {M. 38 .}Transurethral resection for be- 50 min. None 1 mgJkg. Twodoses of 2 min. NgO/Oz.

Male. nign prostatic hyperplasia. (71 mg). 35 mg. each. {M. 34..}Amputntion of finger 58 min. Atropine ling/kg. One dose 2 min-..Pentothal, N O/Og. Mala... (100 mg.) (50 mg). I 3 {\V. 45. }D & C andcone 46 min. Valium nembutal 65 mg 22 mg 1 mni NgO/OQ- Female" 4 {11.30. ...do 21 min. Nembutal, valium, 37.5 mg None 13 min. NgO/OQ- Femalescopolamine. 5 59 }Expl0rat01'y thoracotomy 2.5 hours. Seconal morphine,58 mg do 90 seconds. N /02, 60 mg.

Male. scopOlumine. succinylcholine halothane. 6 {V. 22 }P,ilonidal cyst45 min. Nembutal, atropine. 66 mg do 20-40 NQO/Oz.

--- Male.. seconds.

The preceding examples can be repeated with similar success bysubstituting the generally or specifically described reactants and/or'operating conditions of this invention for those used in the precedingexamples.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

What is claimed is:

l. A sterile injectable composition having general anesthetic,immobilizing muscle relaxant, analgesic, spasmolytic, andanti-convulsant activity comprising an effective amount of the opticalisomer of the alpha racemate of 2-( 2-ethyl-2-phenyl-l ,3-dioxolan-4-yi)piperidine in free base form or as a pharmaceutically acceptable acidaddition salt, substantially free from its isomers, in admixture with apharmaceutically acceptable carrier.

2. The composition of claim 1 adapted for intravenous injection in theform of a pharmaceutically acceptable acid addition salt.

3. The composition of claim 2 as a sterile aqueous solution.

4. The composition of claim 3 wherein the addition salt is thehydrochloride.

l 1. The method of claim 10 wherein the composition 7 is administered asthe hydrochloride acid addition salt.

12. The method of claim 10 wherein the composition is administeredintramuscularly.

13. The method of claim 10 wherein the composition is administeredintramuscularly.

14. The method of claim 13 wherein the composition is administered asthe hydrochloride acid addition salt.

15. The method of claim 13 wherein the mammal is of the feline species.

16. The method of claim 13 wherein the mammal is a primate.

17. A method of inducing general anesthesia in a mammal which comprisesadministering parenterally to the mammal the composition of claim 1 inan amount effective to induce general anesthesia.

18. The method of claim 17 wherein the composition is administered as abasal anesthetic.

19. The method of claim 17 wherein the mammal is a primate.

20. The method of claim 17 wherein the composition is administeredintravenously as a sterile aqueous solution adapted for intravenousadministration.

21. The method of claim 20 wherein the solution contains between about0.5 and 2% of the hydrochloride salt.

V uNiT Eo STATES PATENT CFFICE CERTIFICATE OF CORRECTION patent3,750,077 Dated SeptemberlB, 1973 Charles R. Thompson. 0t :11.

Inventor'(,s)

I It is certified that error appears in the above-identified patent andthat said Letters Patent are hereby corrected as shown below:

Title Page, line 3 of the Title, insert 3 after "1, Column l',f line 3,insert 3 after "1,-", Column 5, line "-16.63" should read +l6.63 line33, "So" should be deleted; line 39, "addtional" should be additionalline 67, "alpha (+)2ethyl-" should be alpha 2- (Z ethyl- Column 6, line48, "'pair" should be paid Column 7,-line 2', "earphon se" should beearphones Claim 12, second line-,dlte "intramuscularly" and replacewithintravenously I .v'Signedifand'sealed'this 15th day of- Otober"1974.

"(sir 1L) 1 ,Attes t:

VCCOY M. GIBSQN JR. I v C. MARSHALL DANN Attesting Officer Commissioner.of Patents FORM PO- I V U5OMM-DC 60376-P69 U 5 GOVERNMENT PRINTINGOFFICE 93o

2. The composition of claim 1 adapted for intravenous injection in theform of a pharmaceutically acceptable acid addition salt.
 3. Thecomposition of claim 2 as a sterile aqueous solution.
 4. The compositionof claim 3 wherein the addition salt is the hydrochloride.
 5. Thecomposition of claim 3 as a 0.1 to 5 percent solution.
 6. Thecomposition of claim 1 adapted for intramuscular injection in the formof a pharmaceutically acceptable acid addition salt.
 7. The compositionof claim 6 as a sterile aqueous solution.
 8. The composition of claim 7wherein the addition salt is the hydrochloride.
 9. The composition ofclaim 7 as a 0.5 to 5.0 percent solution.
 10. A method of at leastcalming a mammal which comprises administering parenterally to themammal the composition of claim 1 in a non-toxic amount effective to atleast calm the mammal.
 11. The method of claim 10 wherein thecomposition is administered as the hydrochloride acid addition salt. 12.The method of claim 10 wherein the composition is administeredintramuscularly.
 13. The method of claim 10 wherein the composition isadministered intramuscularly.
 14. The method of claim 13 wherein thecompoSition is administered as the hydrochloride acid addition salt. 15.The method of claim 13 wherein the mammal is of the feline species. 16.The method of claim 13 wherein the mammal is a primate.
 17. A method ofinducing general anesthesia in a mammal which comprises administeringparenterally to the mammal the composition of claim 1 in an amounteffective to induce general anesthesia.
 18. The method of claim 17wherein the composition is administered as a basal anesthetic.
 19. Themethod of claim 17 wherein the mammal is a primate.
 20. The method ofclaim 17 wherein the composition is administered intravenously as asterile aqueous solution adapted for intravenous administration.
 21. Themethod of claim 20 wherein the solution contains between about 0.5 and2% of the hydrochloride salt.